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Hindawi Publishing CorporationCase Reports in PediatricsVolume 2012, Article ID 459602, 7 pagesdoi:10.1155/2012/459602
Case Report
A Novel 2.3 Mb Microduplication of 9q34.3 Insertedinto 19q13.4 in a Patient with Learning Disabilities
Shalinder Singh,1 Fern Ashton,1 Renate Marquis-Nicholson,1 Jennifer M. Love,1
Chuan-Ching Lan,1 Salim Aftimos,2 Alice M. George,1 and Donald R. Love1, 3
1 Diagnostic Genetics, LabPlus, Auckland City Hospital, P.O. Box 110031, Auckland 1148, New Zealand2 Genetic Health Service New Zealand-Northern Hub, Auckland City Hospital, Private Bag 92024, Auckland 1142, New Zealand3 School of Biological Sciences, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand
Correspondence should be addressed to Donald R. Love, [email protected]
Received 1 July 2012; Accepted 27 September 2012
Academic Editors: L. Cvitanovic-Sojat, G. Singer, and V. C. Wong
Copyright © 2012 Shalinder Singh et al. This is an open access article distributed under the Creative Commons AttributionLicense, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properlycited.
Insertional translocations in which a duplicated region of one chromosome is inserted into another chromosome are very rare. Wereport a 16.5-year-old girl with a terminal duplication at 9q34.3 of paternal origin inserted into 19q13.4. Chromosomal analysisrevealed the karyotype 46,XX,der(19)ins(19;9)(q13.4;q34.3q34.3)pat. Cytogenetic microarray analysis (CMA) identified a∼2.3Mbduplication of 9q34.3 → qter, which was confirmed by Fluorescence in situ hybridisation (FISH). The duplication at 9q34.3 is thesmallest among the cases reported so far. The proband exhibits similar clinical features to those previously reported cases withlarger duplication events.
1. Clinical Report
The proband was born prematurely at 35 weeks gestationwith a birth weight of 2040 g. She required nasogastric tubefeeding during the first week of life. During infancy, shewas investigated for hypotonia and associated plagiocephaly;a brain MRI scan showed no abnormalities. She also haddifficulties swallowing solids until the age of 2 years withongoing tendency to drooling and keeping her mouth open.She walked at 2 years and 3 months of age. Her speech begandeveloping at around that time. At school, she demonstratedage appropriate reading and writing skills, but requiredadditional help in maths. However, the degree of her learningdifficulty was minimal and psychometric assessment wasnot deemed to be necessary. She was also noted to havedifficulties in gross motor and particularly fine motor skillsand required assistance from an occupational therapist. Anophthalmic assessment at 16 years of age demonstratedmyopia, with visual acuity of 6/24 in the right eye and 6/12 inthe left eye. Fundoscopy revealed the presence of pigmentarychanges in both posterior poles.
She was reviewed at the genetics clinic at 16.5 yearsof age. At that time, she was continuing to make goodacademic progress although she was receiving some inputfrom the learning support unit attached to her school. Herheight was at the 50th centile, weight at the 25th centile,and head circumference between the 25th and 50th centiles.Facial dolichocephaly and asymmetry were noted. The eyeswere mildly deep set. She had a short philtrum and mildmicroganthia (Figures 1(a) and 1(b)), with a high archedpalate. There was distal tapering of the fingers with radialclinodactyly of the middle three fingers (Figure 1(c)). Shehad long halluces, curly toes, and bilateral hallux valgus(Figure 1(d)). A mild scoliosis was also noted.
2. Chromosome Analysis
Conventional G-banded chromosome analysis was per-formed on peripheral blood samples taken from the probandand her parents.
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2 Case Reports in Pediatrics
(a) (b)
(c) (d)
Figure 1: Clinical features of the patient at the age of 16.5 years. Frontal view (a) shows the short philtrum. Lateral view (b) shows mildmicrognathia. (c) shows distal tapering of the fingers with radial clinodactyly of the middle three fingers, and (d) shows Long halluces, curlytoes, and bilateral hallux valgus.
Genome-wide copy number analysis was determinedfrom genomic DNA samples using the Affymetrix Cytoge-netics Whole-Genome 2.7 M array, according to the manu-facturer’s instructions. Regions of copy number change werecalculated using the Affymetrix Chromosome Analysis Suitesoftware (ChAS) v.1.0.1 and interpreted with the aid of theUCSC genome browser (http://genome.ucsc.edu/; HumanMar. 2006 (hg18) assembly).
Chromosomal analysis showed a female karyotype46,XX,der(19)ins(19;9)(q13.4;q34.3q34.3) for the proband(Figure 2(a)). The father’s karyotype was 46,XY,ins(19;9)-(q13.4;q34.3q34.3) (Figure 2(d)) and the mother’s karyotypewas normal (data not shown). The array revealed a terminalduplication of approximately 2.3 Mb at 9q34.3, and theproband’s molecular karyotype was arr 9q34.3(137,864,059-140,171,337)x3 (Figure 3; UCSC Genome Browser-NCBIBuild 36, Mar. 2006 assembly).
FISH confirmed that a segment of region 9q34.3 wasinserted into the region 19q13.4 using the locus-specificprobe D9S325, with two signals on the chromosome 9homologues present in the proband (Figures 2(b) and2(c)). FISH using the probe specific for the 19q terminalregion confirmed that the subtelomeres of the derivativechromosome 19 were intact. FISH findings from the fatherdemonstrated an apparently balanced translocation: part ofregion 9q34.3 was inserted into 19q13.4, thus confirming
the parental origin of the derivative chromosome 19 (Fig-ures 2(e) and 2(f)). The duplicated region encompassesapproximately 92 genes, which are likely to contribute to theproband’s phenotypic features.
3. Discussion
Patients with 9q duplications have overlapping features,which include variable degrees of developmental delays,learning or intellectual deficits, facies characterised by dolic-ocephaly, asymmetry, deep set eyes or small palpebral fis-sures, high arched palate, micrognathia and digital anomaliesincluding arachnodactyly, camptodactyly and clinodactyly.Furthermore, the finding of long halluces appears to bea common and distinctive feature in patients with a pureduplication, although many other reported cases carry copynumber changes other than 9q duplications [1–8].
In this study, we report a small ∼2.3 Mb duplica-tion of 9q34.3 detected by CMA. Our patient displayeddolicocephaly and facial asymmetry, mildly deep-set eyes,short philtrum, mild microganthia, high arched palate, clin-odactyly, mild scoliosis, mild myopia, and digital anomalies.A comparison of phenotypic anomalies of our patient withpreviously reported cases is summarised in Table 1.
Recently, Gijsbers et al. [8] reported a 16-year-old girlwith a triplication and duplications in the 9q34.3 region.
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Case Reports in Pediatrics 3
Ta
ble
1:C
linic
alfe
atu
res
inpa
tien
tsw
ith
dupl
icat
ion
and/
ortr
iplic
atio
nof
the
9q34
regi
on.
Cyt
ogen
etic
sH
ouan
dW
ang
[1]
dup
9q32→
q34.
3
Alld
erdi
ceet
al.[
2]du
p9q
34.1→
q34.
3
Spin
ner
etal
.[3]
and
You
ngs
etal
.[4
]adu
p9q
33.3→
qter
Mat
tin
aet
al.[
5]du
p9q
34.1→
qter
Gaw
lik-K
ukl
insk
aet
al.[
6]du
p9q
34.1→
q34.
3
Papa
dopo
ulo
uet
al.[
7]du
p9q3
4.1→
q34.
3
Gijs
bers
etal
.[8]
dup
and
trip
9q34
.3
Pre
sen
tca
sedu
p9q
34.3→
qter
Size
of9q
dupl
icat
ion
dete
rmin
edby
mol
ecu
lar
kary
otyp
e
Un
dete
rmin
edU
nde
term
ined
13.7
9M
bU
nde
term
ined
7.26
Mb
∼5–5
.8M
b
∼0.5
3M
bdu
plic
atio
n;
∼2.4
Mb
trip
licat
ion
∼2.3
Mb
Oth
erch
rom
osom
alan
omal
ies
Nu
llN
ull
Del
12p1
3.33
Du
p21
pter→
q22.
1N
ull
Del
s15
q21.
2-15
q21.
3;15
q22.
31-1
5q23
;15
q25.
1-15
q25.
2
Nu
llN
ull
Clin
ical
feat
ure
sD
olic
ocep
hal
y+
++
∗+
−∗
+Fa
cial
asym
met
ry∗
++
∗+
−+
+D
eep-
set
eyes
/sm
all
palp
ebra
lfiss
ure
s+
++
++
−+
+
Bea
ked
nos
e+
++
+−
+−
−H
igh
arch
edpa
late
++
++
∗+
−+
Mic
rogn
ath
ia/
retr
ogn
ath
ia+
++
∗+
++
+
Ara
chn
odac
tyly
/ca
mpt
odac
tyly
++
++
++
+−
Lon
gh
allu
ces
∗+
++
++
∗+
Scol
iosi
s∗
++
∗+
−−
+Lo
wbi
rth
wei
ght
++
+−
−+
−+
Hyp
oton
ia+
++
++
+−
+Fa
ilure
toth
rive
++
+∗
+−
−−
Car
diac
defe
cts
++
++
−+
−−
Dev
elop
men
tal
dela
y/in
telle
ctu
aldi
sabi
lity
++
++
++
++
aYo
un
gset
al.[
4]is
an18
-yea
rfo
llow
-up
repo
rton
anin
fan
tw
ith
dup
9q34
orig
inal
lyre
port
edby
Spin
ner
etal
.[3]
.∗ N
otre
port
edor
obse
rved
from
publ
ish
edph
otog
raph
s.
-
4 Case Reports in Pediatrics
242322211312
111213
21.121.221.322.122.222.3
313233
34.134.234.3
11
p
q
p
q
13.3
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12111112
13.113.2
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13.4
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q
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11
p
q
9 9
19 der 19
(a)
9qter
9qter9pter
der19
9pter
17cen
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(b)
9qter19qter
19pter
9qter9qter
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(c)
p
q
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p
q
9 der 9
19 der 19
24
232221
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11
24
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13.1
13.2
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13.1
13.2
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(d)
17cen17qter
der199qter
17cen
17pter
9qter
9pterder9
9pter9qter
(e)
9qter
19qter 19pter
9qter
19p1319pter
(f)
Figure 2: Cytogenetics and FISH analysis of proband and father. ((a)–(c)) and (d-f) show the analysis of the proband and father, respectively.Ideograms of chromosomes 9 and 19 show that part of region 9q34.3 is inserted into region 19q13.4 in the proband (a), and the fatheris a carrier of a balanced insertional translocation (panel d). FISH analysis used probes for 9pter (305J7-T7), 9qter (D9S325), 19pter(129F16/SP6), 19qter (D19S238E), 19q13 (GLTSCR1/GLTSCR2/CRX), while 17cen and 17q used control probes ((b)–(c) for the proband,and panels (e)–(f) for the father). These panels confirm that the part of region 9q34.3 is inserted into region 19q13.4. The subtelomeres ofchromosome 19 were intact (the probes for 19pter (129F16/SP6) and 19qter (D19S238E) were used; image not shown).
The authors noted that the clinical features of their probandoverlapped with those in one previous report [2], whichwas a “pure” 9q34.3 duplication case. The same dysmorphicfeatures are shared with the proband reported here, butfeeding difficulties, scoliosis, and severe mental retardationare absent. The more severe phenotype reported by Gijsberset al. [8] may be attributed to a larger ∼2.9Mb region ofduplicated and triplicated subregions (chr9q34:137,265,834-140,207,437) that encompasses approximately 100 genes. Inour case, approximately 92 genes are duplicated in a∼2.3 Mbregion (chr9q34.3 : 137,864,059-140,171,337).
Of the genes contained within the duplicated regiondetected in our patient, eleven are present in the OnlineMendelian Inheritance in Man (OMIM; http://www.ncbi.nlm.nih.gov/omim) morbid map, and of these, all butNOTCH1 are associated with autosomal recessive diseaseand homozygosity for terminating mutations (Table 2). Asa consequence, these OMIM genes do not appear to play arole in the clinical phenotype reported here which is likely tobe caused by gene overexpression, due to the increased copynumber of the 2.3 Mb region of chromosome 9, rather thanhaploinsufficiency.
In the mouse, upregulation of NOTCH activity appearsto be associated with an increase in the number of interneu-ronal contacts and the cessation of neurite growth [9]. In
addition, the NOTCH signalling pathway plays a pivotal rolein embryo development. It is likely, given the mathematicalmodelling undertaken by Raya et al. [10], that increasedexpression of NOTCH1 would have an impact on the levelof NOTCH1-associated subcomplexes, and hence alter devel-opmental and physiological outcomes. That NOTCH1 over-expression may be the principal underlying gene responsiblefor the phenotype of our patient remains speculative atthis stage. It is also possible that the site of insertion onchromosome 19 may affect the expression of chromosome19 genes, which may play a role in the phenotype reportedhere. Unfortunately, the array data does not provide anyclues regarding the specific site of insertion on chromosome19.
In summary, the proband reported here is a new additionto the rare collection of dup 9q34 cases. Our patient hasdeveloped a mild form of the clinical features describedin other 9q34 cases, possibly due to the smaller affectedregion. Patients with shorter dup 9q34 tend to have abetter prognosis and would benefit from special educationwith input from their parents [2]. It is hoped that withincreased reporting of similar cases, dosage changes andbreakpoints in this region can be more clearly correlated tophenotypic features to aid genetic counselling and medicalmanagement.
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Case Reports in Pediatrics 5
Scalechr9: 135500000 136000000 136500000 137000000 137500000 138000000 138500000 139000000 139500000 140000000
Genetic association studies of complex diseases and disorders
OMIM-associated genes
RefSeq genes
9q34.29q34.3
CELABOSURF1
DBH COL5A1 NOTCH1 PTGDSABCA2
GRIN1
602930 602777110300
612277231050
604455268900
600428601541 180245
130010130000120215
608167190198
601895602012
606946
601012607341
605284191100604383604890114840601619606074604606
185642185641185640256000220110185620185630185660
604134274150235400
606813609312223360
601541609012601429
180245
601624
601252605366
611971151675164320173310
612903610224
608129600577262600612860
609491607212
613036613037612854
608582608594603100
612904
609379
612902
610615610167605107
609072
120930612905176803606533600047602030605798612057
604346610537138249
610882606073
609826
241530
602660611180
611255608137
146110
612122
611846611424
610253607001
601012
TSC1TSC1TSC1
GFI1BGFI1B
GTF3C5GTF3C5
CELCELP
RALGDSRALGDS
GBGT1OBP2B
ABOSURF6MED22MED22RPL7A
SNORD24SNORD36BSNORD36ASNORD36C
SURF1SURF2SURF4
C9orf96REXO4
ADAMTS13ADAMTS13ADAMTS13ADAMTS13
C9orf7C9orf7
SLC2A6
SLC2A6
TMEM8C
ADAMTSL2ADAMTSL2
FAM163B
DBH
SARDHSARDH
VAV2VAV2
NCRNA00094
BRD3
WDR5WDR5
RNU6ATAC
RXRACOL5A1
FCN2
FCN2FCN1
OLFM1OLFM1
KIAA0649C9orf116C9orf116
MRPS2LCN1
OBP2APAEPPAEP
LOC100130954LOC100130954
GLT6D1LCN9
SOHLH1SOHLH1
KCNT1CAMSAP1
UBAC1NACC2
C9orf69LHX3LHX3
QSOX2LOC26102
GPSM1
GPSM1GPSM1
DNLZCARD9CARD9
SNAPC4SDCCAG3SDCCAG3SDCCAG3
PMPCAINPP5ESEC16AC9orf163NOTCH1
EGFL7EGFL7
MIR126AGPAT2AGPAT2FAM69B
SNHG7
SNHG7SNHG7
SNORA43SNORA17
LCN10LCN6
LOC100128593
LCN8LCN15
TMEM141KIAA1984
LOC100131193C9orf86C9orf86C9orf86MIR4292C9orf172
PHPT1PHPT1
MAMDC4EDF1EDF1TRAF2FBXW5
C8G
LCN12
PTGDSLCNL1
C9orf142CLIC3
ABCA2
ABCA2C9orf139
FUT7
NPDC1
ENTPD2ENTPD2
C9orf140
UAP1L1
LOC100289341
MAN1B1DPP7GRIN1GRIN1GRIN1GRIN1GRIN1
LRRC26
ANAPC2
SSNA1TPRN
TMEM203
NDOR1NDOR1NDOR1
NDOR1RNF208
C9orf169LOC643596
SLC34A3SLC34A3SLC34A3
TUBB2CFAM166A
C9orf173
COBRA1
C9orf167
NRARP
EXD3
NOXA1
ENTPD8ENTPD8
NELFNELFNELF
NELFNELF
PNPLA7PNPLA7
MRPL41WDR85
ZMYND19
ARRDC1C9orf37EHMT1EHMT1
FLJ40292
MIR602CACNA1B
TUBBP5
chr9 (q34.13-q34.3) p23
Present case
2 MB
Gijsbers et al. [8]
Papadopoulou et al. [7]
Figure 3: Location and extent of 9q34 duplications. UCSC Genome Browser (March 2006 (hg18) assembly) view of the chromosomalregion 9q34.13-q34.3 (chr9:134,776,210-140,171,337) is shown, together with Refseq, OMIM, and GAD genes. The bottom panel shows thelocation and extent of the 9q34.3-qter region of the patient described here, and of other cases reported in the literature. Note: the regionhighlighted in yellow is the ∼2.3 Mb region duplicated in our case, and the thicker green block represents the triplicated region reported byGijsbers et al. [8].
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6 Case Reports in Pediatrics
Table 2: Duplicated region and OMIM genes.
OMIM Protein Gene Disorder Molecular genetics
600577 LIM/homeodomain protein LHX3 LHX3Combined pituitaryhormone deficiency-3
Homozygosity for intragenicdeletion/nonsense mutation
613037 Inositol polyphosphate-5-phosphatase INPP5E Joubert syndrome 1Homozygosity for mutations in theINPP5E gene that lead to decreasedphosphatase activity
Mental retardation, truncalobesity, retinal dystrophy,and micropenis
Homozygous nonsense mutation detectedin the INPP5E gene
607212Caspase recruitment domain-containingprotein 9
CARD9Autosomal recessive formof familial chronicmucocutaneous candidiasis
Homozygous nonsense mutation in theCARD9 gene
190198Notch, Drosophila, homolog of, 1,translocation associated Notch homolog;NOTCH1
NOTCH1 Aortic valve diseaseHeterozygosity for nonsense/frameshiftmutations
Leukemia, T-cell acutelymphoblastic
6031001-Acylglycerol-3-phosphateO-acyltransferase 2
AGPAT2Lipodystrophy, congenitalgeneralised, type 1; CGL1
Homozygous or compound heterozygousmutations
613354 Taperin TPRNAutosomal recessivenonsyndromic deafness-79
Homozygous truncating mutations
604346 Mannosidase, alpha, class 1B member 1 MAN1B1Mental retardation,autosomal recessive 15
Homozygous mutations
138249Glutamate receptor, ionotropic,N-methyl D-aspartate 1
GRIN1Mental retardation,autosomal dominant 8
Missense mutation; in-frame duplicationof codon 560
609826Solute carrier family 34(sodium/phosphate cotransporter),member 3
SLC34A3Hypophosphatemic ricketswith hypercalciuria
Homozygous single-nucleotide deletion
608137Nasal embryonic luteinizinghormone-releasing hormone factor
NELFHypogonadotropichypogonadism
A thr480-to-ala mutation in the NELF gene
607001 Euchromatic histone methyltransferase 1 EHMT1 Kleefstra syndrome
Heterozygous nonsense/frameshiftmutation, in the EHMT1 gene; terminaldeletions, interstitial deletions, derivativechromosomes, and complexrearrangements
The entries in this table were taken from the OMIM database (http://www.ncbi.nlm.nih.gov/omim).
Acknowledgment
The details of this case have been deposited in Deci-pher (https://decipher.sanger.ac.uk); ID 254186. The authorswish to state that there is no conflict of interests withany organization regarding the material presented in thispaper.
References
[1] J. W. Hou and T. R. Wang, “Molecular cytogenetic studiesof duplication 9q32→q34.3 inserted into 9q13,” ClinicalGenetics, vol. 48, no. 3, pp. 148–150, 1995.
[2] P. W. Allderdice, B. Eales, H. Onyett et al., “Duplication 9q34syndrome,” American Journal of Human Genetics, vol. 35, no.5, pp. 1005–1019, 1983.
[3] N. B. Spinner, J. N. Lucas, M. Poggensee, M. Jacquette,and A. Schneider, “Duplication 9q34→qter identified bychromosome painting,” American Journal of Medical Genetics,vol. 45, no. 5, pp. 609–613, 1993.
[4] E. L. Youngs, T. McCord, J. A. Hellings, N. B. Spinner, A.Schneider, and M. G. Butler, “An 18-year follow-up reporton an infant with a duplication of 9q34,” American Journal ofMedical Genetics A, vol. 152, no. 1, pp. 230–233, 2010.
[5] T. Mattina, M. Pierluigi, D. Mazzone, S. Scardilli, C. Perfumo,and F. Mollica, “Double partial trisomy 9q34.1→qter and21pter→q22.11: FISH and clinical findings,” Journal of Medi-cal Genetics, vol. 34, no. 11, pp. 945–948, 1997.
[6] K. Gawlik-Kuklinska, M. Iliszko, A. Wozniak et al., “A girlwith duplication 9q34 syndrome,” American Journal of MedicalGenetics, Part A, vol. 143, no. 17, pp. 2019–2023, 2007.
[7] E. Papadopoulou, C. Sismani, C. Christodoulou, M. Ioan-nides, M. Kalmanti, and P. Patsalis, “Phenotype-genotypecorrelation of a patient with a “balanced” translocation9;15 and cryptic 9q34 duplication and 15q21q25 deletion,”American Journal of Medical Genetics A, vol. 152, no. 6, pp.1515–1522, 2010.
[8] A. C. J. Gijsbers, E. K. Bijlsma, M. M. Weiss et al., “A 400 kbduplication, 2.4 Mb triplication and 130 kb duplication of9q34.3 in a patient with severe mental retardation,” EuropeanJournal of Medical Genetics, vol. 51, no. 5, pp. 479–487, 2008.
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Case Reports in Pediatrics 7
[9] N. Šestan, S. Artavanis-Tsakonas, and P. Rakic, “Contact-dependent inhibition of cortical neurite growth mediated byNotch signaling,” Science, vol. 286, no. 5440, pp. 741–746,1999.
[10] Á. Raya, Y. Kawakami, C. Rodrı́guez-Esteban et al., “Notchactivity acts as a sensor for extracellular calcium duringvertebrate left-right determination,” Nature, vol. 427, no.6970, pp. 121–128, 2004.
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